5J5X

Complex of PKA with the bisubstrate protein kinase inhibitor ARC-1416

Summary for 5J5X

• Entry DOI: 10.2210/pdb5j5x/pdb
• Related: 5IZF 5IZJ
• Descriptor: cAMP-dependent protein kinase catalytic subunit alpha, 47P-AZ1-DAL-DAR-DAR-DAR-DAR, SULFATE ION, ... (5 entities in total)
• Functional Keywords: protein kinase, inhibitor, bisubstrate, oligoarginine, pka, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 42357.33

Authors

Alam, K.A.,Ivan, T.,Uri, A.,Engh, R.A. (deposition date: 2016-04-04, release date: 2016-07-20, Last modification date: 2019-06-19)

Primary citation

Ivan, T.,Enkvist, E.,Viira, B.,Manoharan, G.B.,Raidaru, G.,Pflug, A.,Alam, K.A.,Zaccolo, M.,Engh, R.A.,Uri, A.
Bifunctional Ligands for Inhibition of Tight-Binding Protein-Protein Interactions.
Bioconjug.Chem., 27:1900-1910, 2016

PubMed Abstract: The acknowledged potential of small-molecule therapeutics targeting disease-related protein-protein interactions (PPIs) has promoted active research in this field. The strategy of using small molecule inhibitors (SMIs) to fight strong (tight-binding) PPIs tends to fall short due to the flat and wide interfaces of PPIs. Here we propose a biligand approach for disruption of strong PPIs. The potential of this approach was realized for disruption of the tight-binding (KD = 100 pM) tetrameric holoenzyme of cAMP-dependent protein kinase (PKA). Supported by X-ray analysis of cocrystals, bifunctional inhibitors (ARC-inhibitors) were constructed that simultaneously associated with both the ATP-pocket and the PPI interface area of the catalytic subunit of PKA (PKAc). Bifunctional inhibitor ARC-1411, possessing a KD value of 3 pM toward PKAc, induced the dissociation of the PKA holoenzyme with a low-nanomolar IC50, whereas the ATP-competitive inhibitor H89 bound to the PKA holoenzyme without disruption of the protein tetramer.

PubMed: 27389935
DOI: 10.1021/acs.bioconjchem.6b00293

Experimental method

X-RAY DIFFRACTION (2.6 Å)